Depression

1
How Functional Brain Imaging Can Help Speed Drug
Development and Clinical Trials Depression
Helen S. Mayberg, MD Emory University School of
Medicine ASENT meeting 2012 Washington DC
2
Disclosures

• Grant Support NIMH, CIHR, NARSAD, Dana
  Foundation,
• Stanley Medical Research Fund, Woodruff Fund
• Off-Label Use of Devices DBS electrodes/pulse
  generators
• 1. Medtronics Inc. (U Toronto)
• 2. St. Jude Medical, Inc (Emory)
• Patent US2005/0033379A1 (Andres Lozano,
  co-inventor)
• issued March 2008, St. Jude
  Medical Inc, assignee
• Consultant St Jude Medical Inc /
  Neuromodulation Division
• Emory DBS study FDA IDE G060028 (PI HM)
  Clinicaltrials.gov ID NCT00367003
  devices for research donated by SJM

3
Imaging Wish-List Science, Trials, Care, Devt

• Diagnostic Markers
• illness subtypes (?heterogeneity for clinical
  trials)
• risk identification (pre-symptomatic
  intervention?)
• response predictors (placebo, responders,
  nonresp, resistant)
• relapse, recurrence potential (Tx continuation,
  ID hi risk pts?)
• Evidence Based Treatment Algorithms
• Triage pateints for different trials
• Identify placebo responders in advance of trials
• tailor treatment to what the brain needs
• know in advance what treatments wont work
• Needed studies
• circuit characterization variability genetic,
  clinical correlates
• define treatment specific response pathways
  (psychotx, drug, somatic)
• determine what changes are critical early
  surrogates
• reliability, practicality of such biomarkers in
  individual patients

4

Context Current State of Treatment Options

• Treatments available but one size does not fit
  all
• lt 40 achieve remission (drug, CBT, other)
• placebo response common in trials
• gt 10 become treatment resistant over time
• ECT gt 50-70 Remit but gt 50 relapse in 6
  months
• rTMS 18-24 Resp in 6wks, limited efficacy in
  pt gt 1 failed AD Tx
• VNS 30 Resp at 1yr but lt20 long-term Resp
• ketamine (rapid effects, but unsustained)
• Limits to progress, Innovation
• no pathology, clinical heterogeneity, no
  clear biomarkers
• 50 year focus on monoamines, few new leads
• animal models none capture recurrence,
  relapse, resistance
• overinclusive, nonspecific outcome measures,
  w/ all symptoms treated equally
  (COMPARE TO PD)

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Hypothesis Depression and the Brain
post-natal insults early abuse life
events medical illness
Biological Vulnerability
Exogenous Stressors
gender family history temperament
genetics pre-natal insults
homeostasis
Regions Connections Chemistry
Mood Regulatory Circuits
endophenotypes
recovery
stress
Rx Effects CBT/PT Medication ECT, rTMS, VNS DBS
Subphenotypes MDD, BP Melancholic Atypical Recurre
nt TRD
Depressive episode
Phenotypes
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Defining Depression Circuits 1 Identify circuit
constituents
? MRI volume, Glia
Focal Strokes
? MRI volume
PF
Structure CT, MRI, pathology
PF
Frontal Cingulate hippocampus
Drevets 97 Ongur 98
Robinson 1983
Sheline, 1999
Frontal Cingulate Parietal Also Amygdala Basal
ganglia
Function PET, fMRI EEG
Mayberg 19990 Mayberg
1994, 1997 Kruger 2003
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Defining Depression Circuits 2 Changes with well
characterized treatments
1 week fluoxetine
Subcortical Brainstem Limbic early
Limbic switch Cortex late
6 weeks fluoxetine
Similar time course to neurogenesis, BDNF ?
Mayberg et al. Biol Psychiatry 2000
8
Defining Depression Circuits 2b responder-nonrespo
nder differences
Fluoxetine Responders
Non- Responders
Failure to Switch Non-Response
9
Common Changes Placebo and SSRI Drug Placebo
Plus
Common Cg25 PCg Fr9
Placebo fluoxetine
Also Hc BS
Active Fluxotine
distinguish Placebo R from Active Drug response
with scans?
Am J Psych 159 728-37, 2002
10
Defining Depression Circuits 3 Drug Resp vs
Nonresponders
Baseline
Pre-genual Anterior Cingulate 24
pACC24
F9
?
F9
pACC (r24)
pACC (r24)
Non-responders
Drug responders
Common Frontal change
Multiple interactive Nodes More than 1 area of
Cg involved First clue to potential subtypes
rACC
Mayberg et al NeuroReport 1997
Baseline EEG Theta RgtNR to TCA Pizzagalli AJP 01
11
Hypothesis Scan insultongoing
compensation baseline heterogeneity defines
clinical subtypes
illness is failure to self-correct
over- correction
Trigger
CBT
network
activity
partial
meds
Bad day
symptoms
Hypothesis recovery is optimized by matching
treatment to state of network dysregulation
under
ECT
failed
Depression diagnosis
DBS?
absent
adaptive brain response
Mayberg, J Clin Invest 119717, 2009
12
Proof of Principle Comparison drug to CBT
mF10/9
Change with clinical response
PF9
MCC
PF9
mF9/10 oF11
?
thal
P40
SCC
SSRI (paroxetine) HamD 203 ? 6.74
Cognitive Behavior Therapy HamD 223 ? 64
Suggests Baseline differences Impacting
ultimate Response to a specific Treatment Need
to know if it also Predicts non-response to The
alternative
Goldapple et al. Arch Gen Psych 2004
Kennedy et al. Am J Psych 2001
13
Evolution of Depression Circuit Model Template to
consider different treatments, common effectts
Cognition (attention-appraisal-action)
Par40
PM6
hc
PF9/46
thal
mF9/10
na-vst
Mood state
Emotion Regulation Self-awareness insight
pACC24
amg
mb-sn
oF11
Salience Motivation
Is any one mode Or clinical feature Most critical?
sACC25
hth
bstem
a-ins
Interoception (drive-autonomic-circadian)
Mayberg, Br Med Bul 65193-207, 2003
Mayberg, J Clin Invest 119717, 2009
14
Isolating Key Components focus on negative mood
R
Recovery w/SSRI FDG PET
Transient Sadness CBF PET
F9
F9
ins
ins
Cg25
Cg25
4z
Cg31
?
Cg31
Limbic Cortex Reciprocal Cingulate-Frontal cha
nges
Cg25
Cg25
Cg25
Cg25
- 4z
?
Depressed Patients
Healthy Volunteers
Mayberg et al. Am J Psych 156675-82 1999
15
Critical Role of the Subcallosal Cingulate
? Spines/Dendrites
Sad Memory
Tryptophan Deplete
Cortisol Correlate
?SCC activity
McEwen 1994 etc
Kalin
Mayberg
Talbot
SSRI
SNRI
Placebo
?SCC activity
Mayberg
Mayberg
Kennedy
Hypothesis TRDdysregulated Cg25 connectivity.
Target the problem at its origin
16
Direct Circuit Modulation using DBS block
aberrant sCg25 activity with 2 effect on
connections


MRI target localization
Focus Treatment Resistant Depression
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Toronto Proof of Principle Pilot 6 severe TRD,
GAFlt50 Illness duration avg 5.6 yrs Failed mult
meds, CBT, ECT 6 mo open DBS 4/6 Resp 3/6
remission
Toronto Pilot Proof of principle
Pre-op MRI
Post-op MRI
?
?
Electrode Targeting
Confirm electrode placement
First patient May 13, 2003
Funded by NARSAD, Toronto Western hosp
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Toronto Long-term Followup Emory Sham Controlled
Trial
Remission Response 6 mo 18
41 1 yr 36 36 2 yr 58
65
3-6 yrs, n14
BP-D/MDD N17
24 18 12 6 0
Resp 62.5 46.2 75 64.3
Rem 18.8 15.4 50 42
HDRS-17 score
IT OC
avg42 mo
No change in meds for 6 months
years after implant
BL sham 1m 2 3 4 5 6
7 8 9 10 11 12 2y
Kennedy S, et al. Am J Psych in Adv Feb 1, 2011
Holtzheimer et al. Arch Gen Psych Feb 2012
Lozano A, et al. Biol Psych 64461-67, 2008
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Responder/Nonresponder Differences surgical
precision vs remote effects
Active Contact
Planned Target
cc
g
Non-R
ac
sCg
Resp
Hamani et al J Neurosurg 2009
Simple localization uninformative. Hitting the
target is not the problem
Can this be linked back to patient behavior?
20
Presurgical Response Predictors towards optimal
patient selection resting fMRI
Independent Component Analysis (ICA)
Resting State BOLD fMRI
Similar to PET Can potentially be done in
individuals
Alex Franco, 2011 Holtzheimer et al SOBP 2011
abstract
21
Presurgical Response Predictors towards optimal
patient selection Baseline resting EEG
Similar location to PET and fMRI Confirms
findings, could be a more practical alternative
Broadway, Hilimire , Corballis. GA Tech
unpublished
22
Towards Novel Drug Development Chemical
Specificity within the Cingulate
Ketamine acute
DBS effects
sad induction
Trypt depletion
?
?
?
?
Talbot BP 2004
Deakin AGP 2009
Human Whole Brain Autoradiography
Human Post Mortem
sACC
Hi SERT, 5HT1a
Palomero-Gallagher Human Br Mapping 2009
Arango et al Prog Br Res 2002
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Future Imaging Biomarkers Guide DBS patient
selection and parameter optimization
DTI tractography Define optimal contact
Micro-electrode Lead localization
Resting BOLD fMRI to confirm DBS type
mF
mF
mF10
4 3 2 1
sCg
sCG
SCC25
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Depression DBS Collaborators
Emory Clinical DBS 2005-
Paul Holtzheimer MD Steven Garlow, MD
PhD Patricio Riva Posse MD Dylan
Wint, MD Lori Ritschel PhD
(CBT) C Ramirez PhD (CBT) Sinead Quinn
Kelsey Hagan Megan Filkowski
Andrea Barrocas Margaret Craighead
Andrea Crowell MD

Neurosurgery/Neurology Robert Gross, MD,
PhD Klaus Mewes, PhD Kevin Gotay, MS Donald
Bliwise, PhD Kathryn Rahimzadeh, RN Mahlon
DeLong, MD Thomas Wichmann, MD Psychology/Physiol
ogy Stephan Hamann PhD Cory Inman Otis Smart,
PhD Mike Jutras, PhD Beth Buffalo, PhD Paul
Corballis, PhD (GTech) Matt Hilimire BA (GT) Jim
Broadway PhD (GT) Amy Alderson, PhD (NPsy)
Johns Hopkins 1985-91 UTHSCSA 1991-98
Toronto 1999-2004 Andres Lozano MD PhD Sidney
Kennedy MD Clement Hamani MD Zindel Segal PhD
(CBT)
Emory Depression Biomarkers Ed Craighead Boadie
Dunlop Tanja Mletzko CB Nemeroff
Imaging Lab
Alex Franco, PhD Callie McGrath, BS
KiSueng Choi, MS Mary Kelley, PhD
David Gutman, MD C Craddock, PhD
Jared Moreines, BS
Yerkes/Animal Models Donald Rainnie PhD Teresa
Madsen BS Leonard Howell PhD Mar Sanchez PhD Sue
Tye, PhD (AUST) Clement Hamani MD (TO) S Pannu
PhD (Berkeley) M Ghovanloo PhD (GTech)
External Collaborators H Johansenberg PhD (UK) N.
P-Gallagher PhD (GR) C McIntyre PhD (Ohio)
Grants NARSAD, Woodruff Fund, Emory Healthcare,
Stanley Medical Research Institute, Dana
Foundation, NSF CBN Venture, K23
MH077869,R01MH073719, P50MH077083, RO1MH080880